The development of IN inhibitors is described in an extensive body of scientific and patent literature. From this work, Raltegravir (RAL) has emerged as the first FDA-approved AIDS therapeutic (October 2007) that functions as an IN inhibitor. More recently (August 2012), Elvitegravir (EVG) has joined Raltegravir as the second FDA-approved IN inhibitor. Both RAL and EVG show a low to moderate genetic barrier to resistance, and extensive cross-resistance. Therefore, second-generation inhibitors continue to be developed in efforts to achieve greater efficacy against RAL (and EVG)-resistant strains of IN. Although a number of promising second-generation inhibitors have been brought forward, in vitro selection of IN mutants showing reduced sensitivity to many second-generation agents is also being found. That it is possible to design IN inhibitors with improved genetic barriers that preserve activity against some RAL and EVG resistant strains is evidence by Dolutegravir (DTG), which is in late stages of clinical trials. However, even DTG is subject to development of resistant strains of IN. Therefore, the focus of research in this field today is to gain a better understanding of structural parameters leading to resistance and the development of new agents that exhibit improved profiles against the major resistant strains of IN. Although a number of promising second-generation inhibitors have been brought forward, in vitro selection of IN mutants showing reduced sensitivity to many second-generation agents is also being found. That it is possible to design IN inhibitors with improved genetic barriers that preserve activity against some RAL and EVG resistant strains is evidence by Dolutegravir (DTG), which is in late stages of clinical trials. However, even DTG is subject to development of resistant strains of IN. Therefore, the focus of research in this field today is to gain a better understanding of structural parameters leading to resistance and the development of new agents that exhibit improved profiles against the major resistant strains of IN. Utilizing the synthetic expertise of my laboratory, we have teamed with pharmacologists (Dr. Yves Pommier, NCI), virologists (Dr. Hughes, NCI) and structural biologists (Dr. Cherepanov, London Research Institute) to develop new IN inhibitors that maintain efficacy against the major strains of resistant IN mutants. We have developed sulfonamide-containing bicyclic 6,7-dihydroxyoxoisoindolin-1-one-based IN inhibitors that exhibit better absolute efficacies than RAL against the clinically relevant Y143R IN mutant and with selectivity indexes (SI = ratio of CC50 to EC50) values exceeding 100. In collaboration with Dr. Peter Cherepanov we have obtained co-crystal studies of our inhibitors bound to the prototype foamy virus (PFV) intasome, which include complexed DNA substrate. Because PFV has high homology to HIV, these structures provide valuable insight into probable inhibitor interactions with HIV. These structures show that our inhibitors bind in the active site in fashions similar to those reported for other IN inhibitors, such as RAL. Molecular dynamics analyses of the HIV-1 intasome highlighted the importance of the viral DNA in drug potency and their ability to show reduced loss of potency against the Y143R mutant form of IN, which is a significant RAL-resistant form of the enzyme. In more recent work we have developed a new class of IN inhibitors that exceed the efficacies of the current clinical agents, RAL and EVT in cellular infectivity models employing a panel of the major resistant mutant forms of IN. Certain of these analogs exhibit selectivity indices greater than 20,000, with inhibitory profiles against the panel of IN mutants that significantly exceed RAL and equal or exceed those of DTG, which is one of the most promising second-generation IN inhibitors in current clinical trials.